Calcineurin/NFAT (Nuclear Factor of Activated T-cells) signaling is involved in multiple aspects of skeletal muscle development and disease. A number of studies demonstrate that calcineurin plays a regulatory role in skeletal muscle adaptation and muscle regeneration by its ability to promote myotube differentiation. Calcineurin dephosphorylates members of NFAT transcription factors allowing NFAT translocation into the nucleus where it cooperates with other transcription factors to induce transcription of target genes. We demonstrated that calcineurin/NFATc3 signaling is required for primary myogenesis by transcriptional cooperation with the basic helix loop helix transcription factor MyoD (Armand et al., 2008) We now show that the NFATc2 isoform is also able to physically interact with MyoD. However, NFATc2 and MyoD interaction is unique, since the interacting domains are different from those involved in the NFATc3/MyoD interaction. The biological significance of such NFATc2/MyoD interaction is completely unknown and is likely crucial as myod:nfatc2 double deletion is lethal. Our in vitro and in vivo studies show that MyoD and NFATc2 cooperate to regulate muscle fiber formation and specification during secondary myogenesis: we have indeed revealed a significant muscle aplasia in the double mutant nfatc2/myod embryos and a specific fall of expression of the neonatal myosin heavy chain (MHC) in double mutants. Altogether these data show that NFATc2 and MyoD cooperate in vivo during late myogenesis. Now, using microarray strategy, we focus on the target genes regulated by the NFATc2/MyoD complex. Armand et al. 2008. J Biol Chem. 283 : 29004-10

Spinal Muscular Atrophy (SMA), a lethal neurodegenerative disease which occurs in childhood, is due to the misexpression of the survival-motor-neuron (SMN) proteinin motor-neurons. We have evaluated the effect of a running-based training (Grondard et al., 2005) on type 2 SMA-like mice Smn _7/_7, Smn2+/+ (Hsieh-Li et al.,2000). The results have shown a gain in motor function and life span (+60%), an acceleration of muscles and neuromuscular junctions maturation, a reduction ofmotor-neurons death in the lumbar anterior horn of the spinal cord and an increase in exon7-containing SMN transcripts. We have also shown that the specific inhibitionof NMDA-receptor abolished the exercise-induced effects (Biondi et al., 2008).In the present work, we demonstrate the benefits of an adequate NMDA-receptor activation(5 pmol/g/d in 0.9% NaCl) in the type 2 SMA-like mice. This treatment significantly accelerated motor-unit postnatal maturation, counteracted motor-neurons deathin the spinal cord and induced a marked increase in SMN expression resulting from the insertion of the exon 7 in the SMN transcripts generated from SMN2 gene.Furthermore, the type 2 SMA-like mice lifespan is considerably extended. The analysis of the intracellular signaling cascade that lay downstream the activated NMDAreceptorrevealed an unexpected reactivation of the CaMKII/AKT/CREB pathway that induced an enhanced SMN expression. Therefore, pharmacological activation ofspinal NMDA-receptors could constitute a useful strategy for both increasing SMN expression and limiting motor-neurons death in SMA spinal cord.